Journal of Thoracic Oncology最新文献

Introduction: HER2 mutations define a distinct, therapeutically actionable subset of non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has demonstrated strong activity in clinical trials, but real-world data are limited.

Methods: We conducted a retrospective, multinational cohort study of patients with advanced HER2-mutant NSCLC treated with T-DXd outside clinical trials between August 2021 and January 2025 across 68 centers in Europe and Israel. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety.

Results: Among 168 patients (median age 62 years; 59% female; 56% never-smokers), the ORR was 54.8% (95%CI, 46.9-62.4) and disease control rate 88.7% (95%CI, 82.9-93.1). Median PFS was 7.2 months (95%CI, 6.2-9.7) and OS 18.3 months (95%CI, 13.3-24.8). Treatment-naïve patients (n=18) achieved an ORR of 72.2% (95%CI, 46.5-90.3) and median OS of 22.1 months (95%CI, 10.0-NE). Patients with measurable brain metastases (n=27) had an intracranial ORR of 74.1% (95%CI, 53.7-88.9), including 25.9% complete responses. Grade ≥3 treatment-related adverse events occurred in 32% of patients. Interstitial lung disease (ILD)/pneumonitis occurred in 14% (four fatal cases) of patients, without consistent predictors.

Conclusions: In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naïve patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with ILD remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.

Purpose: Clinical trial designs marked by extensive data collection, restrictive eligibility, and lengthy protocols create inefficiencies, increase costs, and hinder accrual. These are further compounded by staffing shortages and operational burdens. By incorporating pragmatic features including simplified eligibility criteria, streamlined protocol, and data collection, the PROSPECT-Lung trial paves the way forward as a model for enhancing clinical trial efficiency and feasibility, while maintaining scientific rigor.

Patients and methods: PROSPECT-Lung (CTIU2317-A082304-S2402) is a pragmatic, phase III, open-label, randomized trial comparing 3-year real-world event-free survival and overall survival using approved perioperative and adjuvant immunotherapy-based treatment strategies in patients with resectable non-small cell lung cancer. Protocol length and data collection elements were compared with Alliance A081801, Integration of Immunotherapy into Adjuvant Therapy for Resected NSCLC: ALCHEMIST CHEMO-IO (ClinicalTrials.gov Identifier: NCT04267848), a phase III trial in the same disease setting, to quantify streamlining efforts.

Results: Relative to A081801, PROSPECT-Lung achieved major reductions in trial complexity. Protocol length decreased from 88 to 30 pages (65%), and data fields per patient were reduced from 2523 to 438 (82.6%), driven by streamlined summary versus cycle-by-cycle data collection. These efficiencies translate to estimated site workload reductions from 210 hours per patient in A081801 to 36.5 hours in PROSPECT-Lung. At full accrual, this equates to more than 190,000 hours saved in chart review, data entry, documentation, and quality control.

Conclusion: By broadening eligibility and streamlining logistics, PROSPECT-Lung reduces burden for patients, investigators, and sites while preserving scientific integrity. This pragmatic approach, when appropriate and possible, provides a replicable model for future cancer trials, promoting efficiency, accessibility, and real-world relevance.

Circulating tumor DNA (ctDNA) has emerged as an important prognostic factor in cancer patients. Management of early stage non-small cell lung cancer (NSCLC) remains challenging with a high rate of disease recurrence. In this prospective cohort, 153 patients with clinical stage I NSCLC (75.8% pathologic stage I) underwent real-time plasma ctDNA testing using a tumor-informed whole exome sequencing approach, RaDaR™. Pre-operative ctDNA was detected in 22.4% of patients (6 weeks median turnaround time) and was significantly associated with recurrence free survival (RFS, HR 3.81, p=0.006). No patients with pathologic stage I disease had detectable post-operative ctDNA. The 2-year RFS was 84.2%, with inferior outcomes among patients with pre-operative ctDNA detected (69.1%). In pathologic stage I NSCLC, preoperative ctDNA detection and invasive tumor size remained independently associated with RFS. Here, we demonstrate the clinical feasibility of plasma ctDNA to inform treatment decision-making in stage I NSCLC. ClinicalTrials.gov identifier: NCT05254782.

Despite recent advances in the treatment of pleural mesothelioma, it remains a challenging and heterogeneous disease, with limited options for patients. Survival rates have only marginally improved in the past years, highlighting the need for a better biological understanding of the disease for the translation into clinical practice. Although recent years have seen substantial progress in genomics and molecular pathology, much of the existing literature has focused on morphology-correlated changes, with molecular, immunohistochemical, clinical, and blood biomarkers largely studied in a correlative framework. Despite these efforts, TNM classification remains the most powerful predictor of survival and one of the most important parameters to guide therapy in clinical practice. However, emerging evidence reveals that histology alone fails to capture the full heterogeneity of the disease, leading to suboptimal diagnostic, prognostic, and therapeutic approaches. This review summarizes recent major molecular findings relating not only to histology but also ploidy, tumor microenvironment, and methylation-which together offer a more comprehensive understanding of interpatient heterogeneity. In light of these results, we discuss the potential for a new morpho-molecular classification based on these molecular findings to overcome the current clinical challenges. Future directions for the field are also proposed, including the potential for emerging technologies such as single-cell, spatial omics, and artificial intelligence to fill in the gaps of bulk studies and unveil clinically relevant information about pleural mesothelioma tumor heterogeneity.

Introduction: Low-dose computed tomography (LDCT) screening saves lives but is limited by high false-positive rates, necessitating noninvasive risk stratification. The prospective Bio-Multicentric Italian Lung Detection (BioMILD) trial was the first to validate the combination of a plasma microRNA test (MSC) with LDCT to personalize screening intervals. This study integrates a novel immune signature classifier (ISC), based on peripheral blood mononuclear cell profiling, to complement MSC, maximize information from a single blood draw, and further optimize the management of suspicious lung nodules.

Methods: Plasma and peripheral blood mononuclear cell samples were prospectively collected from 304 heavy smokers enrolled in the BioMILD trial who presented with LDCT-detected suspicious nodules and a 7.5-year median follow-up. MSC and ISC tests were determined by real-time quantitative polymerase chain reaction. Grafting of patient-derived xenograft models, obtained from the same patients, was used as indicator of tumor aggressiveness.

Results: ISC was associated with age (p = 0.0323) and Lung-RADS (p = 0.0008) and was significantly higher in patients with cancers diagnosed within 2 years (p = 0.0006). Higher ISC values also correlated with successful patient-derived xenograft engraftment (p = 0.0449). In terms of diagnostic performance, the combined ISC and MSC model achieved 96% sensitivity and 98% negative predictive value (NPV) (95% confidence interval: 0.93-0.99). It represented a significant enhancement than MSC alone (ΔNPV = +0.05; 95% confidence interval: 0.01-0.08) and resulted in a 37% reduction of false positives.

Conclusion: Integration of immune and molecular markers significantly enhances LDCT screening accuracy. The higher NPV achieved by the combined model allows greater confidence in ruling out malignancy among LDCT-detected nodules, thereby reducing unnecessary follow-up examinations and invasive procedures.